Cardiovascular diseases and cancer are very common in Western countries and these disease groups are economically important because patients suffering from them typically lose large amounts of work time and must be treated for prolonged periods. Blood vessels play an important role in the evolution of cardiovascular diseases, as well as in the pathogenesis of cancer. A central role in the pathogenesis of vascular diseases is played by endothelial cells lining the inner walls of blood vessels. Traumas and metabolic disturbances in endothelial cells give rise to so-called atheroma plaques and to arteriosclerosis. Neovascularization, induced by tumor cells via growth factors stimulating endothelial cells, is an important event in various cancers. It is known from experimental investigations that in order to develop and grow, cancer cells need neovascularization to ensure transport of nutrients and oxygen into the growing tissue.
The cellular behavior responsible for the development, maintenance, and repair of differentiated cells and tissues is regulated, in large part, by intercellular signals conveyed via growth factors and similar ligands and their receptors. The receptors are located on the surface of responding cells and they bind peptide or polypeptide growth factors, as well as other hormone-like ligands. As a result of this interaction, rapid biochemical changes occur in the responding cells which lead to a rapid and a long-term readjustment of cellular gene expression. Several receptors associated with various cell surfaces may bind specific growth factors.
Tyrosine phosphorylation is one of the key modes of signal transduction across the plasma membrane. Several currently-known protein tyrosine kinase genes encode transmembrane receptors for polypeptide growth factors and hormones, such as epidermal growth factor (EGF), insulin, insulin-like growth factor (IGF-I), platelet derived growth factors (PDGF-AA, AB and BB), and fibroblast growth factors (FGFs). See e.g., Heldin et al., Cell Reg., 1:555-556 (1990); Ullrich, et al., Cell, 61:2243-354, (1990). Endothelial cells growth factor receptors are of particular interest due to the possible involvement of growth factors, such as FGFs, in several important physiological and pathological processes including angiogenesis, arteriosclerosis and inflammatory diseases (Folkman, et al., Science, 235:442-447, 1987). Also, the receptors of several hematopoietic growth factors are tyrosine kinases. These include the colony stimulating factor 1 receptor (Sherr et al., Cell, 41:665-676, 1985) and c-kit, the stem cell factor receptor (Huang et al., Cell, 63:225-233, 1990).
The receptor tyrosine kinases may be divided into evolutionary subfamilies, on basis of structural similarities and differences, these proteins differ in their specificity and affinity (Ullrich et al., supra). In general, receptor tyrosine kinases are glycoproteins which comprise an extracellular domain, capable of binding the growth factor, a transmembrane domain, which usually is an .alpha.- helical portion of the protein, a juxtamembrane domain, where the receptor may be regulated by, e.g., protein phosphorylation, a tyrosine kinase domain, which is the enzymatic component of the receptor and a carboxy terminal tail, which, in many receptors, is involved in recognition and binding of specific substrates.
Recently, a novel endothelial cell receptor tyrosine kinase, called Tie, has been described in co-owned International Patent Publication WO 93/14124. Tie is an acronym corresponding to tyrosine kinase containing immunoglobulin- and EGF-like domains. Tie is useful in the diagnosis and treatment of certain diseases involving endothelial cells and their associated Tie-receptors, such as neoplastic diseases involving tumor angiogenesis, wound healing, thromboembolic diseases, atherosclerosis, and inflammatory diseases.